INTEGRATED VIRTUAL SCREENING AND ADMET EVALUATION OF IMIDAZOLE DERIVATIVES TARGETING GSK-3Β AS POTENTIAL ANTICANCER AGENTS

Abstract

Glycogen Synthase Kinase -3β (GSK-3β) is a multifunctional serine/ threonine protein kinase interfere in the regulation of cell proliferation, apoptosis, metabolism and multiple oncogenic signalling pathways. GSK-3β has been linked with progression of several human malignancies, making it protein target for anticancer drug discovery. In this present study aimed to find out newly designed imidazole derivatives (coded as IMD1–IMD5) as potential GSK-3β inhibitors using an integrated in silico drug discovery approach. In silico study evaluate that all five imidazole derivatives exhibited favourable binding affinities toward the catalytic pocket of GSK-3β, with docking scores from −8.09 to −8.88 kcal/mol. Among the evaluated compounds, IMD1 and IMD3 showed the highest binding affinity (−8.88 kcal/mol), followed by IMD4 (−8.58 kcal/mol), IMD2 (−8.17 kcal/mol), and IMD5 (−8.09 kcal/mol). Interaction analysis revealed that the ligands established multiple favourable contacts with critical active-site residues, including LYS85, MET101, VAL110, LEU132, TYR134, VAL135, CYS199, ASP200, PHE201, and LEU188, through hydrogen bonding, π–π stacking, π alkyl, π–sigma, and hydrophobic interactions, indicating stable accommodation within the ATP-binding cavity. SwissADME analysis indicated that all derivatives complied with Lipinski's Rule of Five, exhibiting molecular weights below 500 Da, acceptable lipophilicity (LogP < 5), suitable TPSA values, and favourable hydrogen-bonding characteristics without significant drug-likeness violations. The compounds also evaluated promising oral bioavailability and physicochemical properties suitable for further optimization. These findings support the potential of this imidazole scaffold as a promising lead for the design of novel GSK-3β-targeted anticancer agents.